Pathophysiology Defined by Altered Signal Transduction Pathways:  The Role of JAK-STAT and PI3K Signaling in Leukemic Large Granular Lymphocytes

Schade, Andrew E.; Wlodarski, Marcin W.; Maciejewski, Jaroslaw P.

doi:10.4161/cc.5.22.3449

Cited by 47 publications

(38 citation statements)

References 35 publications

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“…There is evidence for diverging roles of specific signaling pathways in CD8 ϩ T-cell and CD4 ϩ T-cell biology. For example, specific roles for the AP-1 32 and IL-6/STAT3 33 signaling pathways have been reported in the context of cytotoxic T-cell proliferation (AP-1) and survival (IL-6/STAT3). In the absence of known direct toxic effect of doxycycline on cytotoxic T cells, 17 we speculate that the selective reduction of cytotoxic T cells on doxycycline treatment may be mechanistically linked to the reduced AP-1 and/or STAT-3 activation after doxycycline therapy.…”

Section: Discussionmentioning

confidence: 99%

Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm

et al. 2009

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Background-Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a clinical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on vascular inflammation. Methods and Results-Sixty patients scheduled for elective open aneurysmal repair were randomly assigned to 2 weeks of low-, medium-, or high-dose doxycycline (50, 100, or 300 mg/d, respectively) or no medication (control group). Aortic wall samples were collected at the time of operation, and the effect of doxycycline treatment on vascular inflammation was evaluated. Independently of its dose, doxycycline treatment resulted in a profound but selective suppression of aortic wall inflammation as reflected by a selective 72% reduction of the aortic wall neutrophils and a 95% reduction of the aortic wall cytotoxic T-cell content (median values; PϽ0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways (PϽ0.0158, NS) and reduced vascular interleukin-6 (PϽ0.00115), interleukin-8 (PϽ0.00246, NS), interleukin-13 (PϽ0.0184, NS), and granulocyte colony-stimulating factor (PϽ0.031, NS) protein levels. Doxycycline was well tolerated; there were no adverse effects. Conclusions-A brief period of doxycycline treatment has a profound but selective effect on vascular inflammation and reduces aortic wall neutrophil and cytotoxic T-cell content. Results of this study are relevant for pharmaceutical stabilization of the abdominal aneurysm and possibly for other inflammatory conditions that involve neutrophils and/or cytotoxic T cells.

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Section: Discussionmentioning

confidence: 99%

Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm

et al. 2009

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“…3 Similar to normal activated CTLs, leukemic T-LGLs exhibit activation of multiple survival-signaling pathways. 4,5 Among these, the Janus Kinase/signal transducer and activator of transcription (JAK/ STAT) intracellular pathway has been associated with LGL transformation. Particularly, it was found that signal transducer and activator of transcription-3 (STAT3) protein, a key component of this signaling, is highly expressed and is constitutively activated in leukemic LGLs compared with peripheral blood mononuclear cells (PBMCs) of healthy individuals.…”

Section: Cd57mentioning

confidence: 99%

Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia

Teramo

Gattazzo

Passeri

et al. 2013

Blood

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Key Points• In T-LGLL, autologous LGLdepleted PBMCs release high levels of IL-6 contributing to the constitutive STAT3 activation in leukemic LGL. • LeukemicLGLs show SOCS3 down-modulation, which is responsible for lack of the negative feedback mechanism controlling STAT3 activation.The JAK/STAT pathway is altered in T-cell large granular lymphocytic leukemia. In all patients, leukemicLGLs display upregulation of phosphorylated STAT3 (P-STAT3) that activates expression of many antiapoptotic genes. To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays, we analyzed interleukin (IL)-6 and suppressor of cytokine signaling-3 (SOCS3), 2 key factors of the JAK/STAT pathway that induce and inhibit STAT3 activation, respectively. We showed that IL-6 was highly expressed and released by the patients' peripheral blood LGL-depleted population, accounting for a trans-signaling process. By neutralizing IL-6 or its specific receptor with specific antibodies, a significant reduction of P-STAT3 levels and, consequently, LGL survival was demonstrated. In addition, we found that SOCS3 was down-modulated in LGL and unresponsive to IL-6 stimulation. By treating neoplasticLGLs with a demethylating agent, IL-6-mediated SOCS3 expression was restored with consequent P-STAT3 and myeloid cell leukemia-1 down-modulation. Methylation in the SOCS3 promoter was not detectable, suggesting that an epigenetic inhibition mechanism occurs at a different site. Our data indicate that loss of the inhibitor SOCS3 cooperates with IL-6 to maintain JAK/STAT pathway activation, thus contributing to leukemic LGL survival, and suggest a role of demethylating agents in the treatment of this disorder. (Blood. 2013;121(19):3843-3854)

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“…42 This study indicates that the allele may be shuttled to the apical surface aberrantly because of the absence of a sorting motif normally found on the cytoplasmic tail. In the context of additional somatic events such as the common anti-apoptotic abnormalities of Fas-FasL, PI3K-AKT, and STAT3 previously described in LGL leukemia, [43][44][45][46] MICA may simply represent a functional predisposition to autoimmunity.…”

Section: Discussionmentioning

confidence: 95%

MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia

Viny¹,

Clemente²,

Jasek³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundLarge granular lymphocyte leukemia is a semi-autonomous clonal proliferation of cytotoxic T cells accompanied by immune cytopenias and various autoimmune conditions. Due to the rarity of this disease and its association with autoimmune diseases, a theoretical germline or somatic mutation might have significant penetrance, thus enabling detection, even from samples of suboptimal size, through genome-wide association studies. Design and MethodsTo investigate a non-mendelian genetic predisposition to large granular lymphocyte leukemia, we used a step-wise method for gene discovery. First, a modified 'random forests' technique was used for candidate gene identification: this was followed by traditional allele-specific polymerase chain reaction, sequencing modalities, and mechanistic assays. ResultsOur analysis found an association with MICA, a non-peptide-presenting, tightly regulated, stress-induced MHC-like molecule and cognate receptor for NKG2D, found abundantly on large granular lymphocyte leukemia cells. Sequencing of germline DNA revealed a higher frequency of MICA*00801/A5.1 in patients with large granular lymphocyte leukemia than in matched controls (64% versus 41%, P<0.001, homozygous 40% versus 15%, P<0.001). Flow cytometry was employed to determine the expression of MICA within hematologic compartments, showing that the signal intensity of MICA was increased in granulocytes from neutropenic patients with large granular lymphocyte leukemia in comparison with that in controls (P=0.033). Furthermore, neutrophil counts were inversely correlated with MICA expression (R 2 =0.50, P=0.035). Finally, large granular lymphocyte leukemia cells were able to selectively kill MICA + Ba/F3 lymphocytes transfected with human MICA*019 in a dose-dependent manner compared to naïve cells (P<0.001), an effect mitigated by administration of an anti-NKG2D antibody (P=0.033). ConclusionsOur results illustrate that MICA-NKG2D played a role in disease pathogenesis in the majority of patients in our cohort of cases of large granular lymphocyte leukemia and further investigation into this signaling axis may provide potent therapeutic targets. Haematologica 2010;95(10): 1713-1721. doi:10.3324/haematol.2010 MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia © F e r r a t a S t o r t i F o u n d a t i o n

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Pathophysiology Defined by Altered Signal Transduction Pathways: The Role of JAK-STAT and PI3K Signaling in Leukemic Large Granular Lymphocytes

Cited by 47 publications

References 35 publications

Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm

Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm

Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia

MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia

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